Until recently, the localization of intravascular drugs in body tissues has depended on chemical partitioning across microvascular barriers into the tissue compartments of multiple body organs. This resulted in only 0.01% to 0.001% of the injected dose actually reaching the intended targets. Approximately 20 years ago, drugs were entrapped in liposomes and microspheres. This modified the initial biodistributions and redirected them to phagocytes in the reticuloendothelial organs: liver, spleen and bone marrow. In 1978, the present inventor and coworkers developed a means to co-entrap drug plus magnetite in microspheres which could be injected intravenously and localized magnetically in the tissue compartments of nonreticuloendothelial target organs (e.g., lung and brain). Magnetic capture was accomplished by selective dragging of the particles through the vascular endothelium into normal tissues and tissue tumors positioned adjacent to an extracorporeal magnet of sufficient strength (0.5 to 0.8 Tesla) and gradient (0.1 Tesla/mm). Although this technique was highly efficient and deposited between 25% and 50% of an injected dose in the desired target tissue, it was also a very complicated approach which had the following major disadvantages: 1) restriction of use to specialized medical centers; 2) permanent disposition of magnetite in target tissue; 3) focal overdosing of drug due to inhomogeneity of the capturing magnetic field; and 4) application to a very limited number of therapeutic agents. In the process of studying magnetic targeting, however, it was learned that slow (controlled) release of toxic drugs from entrapment-type carriers (microspheres) protected the normal cells within the local tissue environment from drug toxicity and still gave effective treatment of tumor cells and microorganisms. At the time when monoclonal antibodies became generally available for animal and clinical research, it was hoped that antibody-drug conjugates would limit the biodistribution of toxic agents and cause them to become deposited in foci of disease (tumors and infections) which were located across the microvascular barrier within target tissues. Unfortunately, most monoclonal antibodies were (and are still) obtained from mice, making them foreign to human recipients. Conjugation of drugs at therapeutically relevant substitution ratios makes the derivatives even more foreign and impairs their binding specificities. Hence, antibody-drug conjugates are cleared rapidly by the liver, in a fashion similar to that for liposomes. Importantly, their localization in most solid tumors is even further impaired by the presence of a partially intact microvascular barrier which separates the tumor tissue (interstitium) from the bloodstream. This allows only about 1% to 7% (at best) of the injected dose to reach nonreticuloendothelial targets. Selected lymphomas and leukemias provide exceptions to this rule because of a greater natural breakdown of this vascular barrier. However, for the vast majority of solid tumors and infections, a general-purpose method is still needed to deliver drugs efficiently across microvascular barriers in a depot (controlled release) form. This depot form of drugs is necessary in order to protect vascular endothelium and normal tissue cells from the toxic effects of drugs, protect drug from endothelial and tissue metabolism during transit, and make drug bioavailable at a controlled therapeutic rate within the target tissues and tissue lesions.
Active endothelial transport has been demonstrated for small molecules (e.g., glucose and insulin), however, no studies other than that of the present inventor. Present examples show that transendothe migration of particles and molecular aggregates larger than about 2 nm. in diameter are accelerated by the application of surface coatings which bind multiply to receptors or antigens which are either synthesized by endothelium or are synthesized at other sites but become tightly associated with the endothelial surface. (Ranney, Biochem. Pharmacology, V. 35, No. 7, pp. 1063-1069 (1986)).